Infusion of cerebrospinal fluid from morphine tolerant rats into naive rats renders the recipients less susceptible to the acute analgesic effects of morphine as measured by tail-flick latency response. The metabolites of morphine-tolerant vs. acutely treated rats have been studied to determine if this phenomenon is related to a brain specific metabolite. No differences were detected in cerebrospinal fluid opiate receptor binding capacity between the animal groups. Tolerant animals had significantly less conjugated morphine in both csf and urine than acutely treated animals. The principle in the csf of morphine-tolerant rats responsible for blunting the morphine analgesic response in naive animals is likely to be an endogenous agent.